Regulation Of Mitotic Transcription By Centromeres

The iconic X shape of condensed mitotic chromosomes has been described in the 19th century, but we still know little about the structural organization of mitotic chromosomes and its consequences on chromatin functions such as transcription. Until recently, the mechanisms leading to chromosome condensation during mitosis were thought to involve the diffusion of chromatin compaction signals across nuclei, resulting in complete shut down of gene expression. We have recently challenged this model by revealing that in fact, condensation is licensed by a single locus, the centromere, and spreads along chromosome arms in a chromosome-autonomous manner. In parallel, other studies uncovered a mitotic-specific transcription program, showing that mitotic chromatin is actually not silent. However, the molecular mechanisms establishing and maintaining mitotic transcription are yet unknown. This project seeks to uncover the mechanisms regulating mitotic transcription. And based on previous work and preliminary data, we hypothesize that in addition to licensing chromatin condensation, the centromere controls mitotic and interphase gene expression. Upon completion of this project we expect to have identified a new centromere-dependent molecular mechanism regulating chromatin dynamics and transcription, which will provide deeper insight into general mechanisms of gene expression. Thus far, we have already revealed and published that mitotic chromosome condensation resets the chromatin to maintain physiological levels of gene expression outside mitosis and thus safeguard cellular identity. We then plan on expending our scope to the role of centromeres in cancer and processing of harmful non-chromosomal DNA molecules like viruses by the cell.

The iconic X shape of condensed mitotic chromosomes has been described in the 19th century, but we still know little about the structural organization of mitotic chromosomes and its consequences on chromatin functions such as transcription. Until recently, the mechanisms leading to chromosome condensation during mitosis were thought to involve the diffusion of chromatin compaction signals across nuclei, resulting in complete shut down of gene expression. We have recently challenged this model by revealing that in fact, condensation is licensed by a single locus, the centromere, and spreads along chromosome arms in a chromosome-autonomous manner. In parallel, other studies uncovered a mitotic-specific transcription program, showing that mitotic chromatin is actually not silent. However, the molecular mechanisms establishing and maintaining mitotic transcription are yet unknown. This project seeks to uncover the mechanisms regulating mitotic transcription. And based on previous work and preliminary data, we hypothesize that in addition to licensing chromatin condensation, the centromere controls mitotic and interphase gene expression. Our specific aims are to 1) circumscribe the centromere-regulated transcriptome, 2) characterize the gene regulatory factors that are specifically impacted by centromeres at centromere-dependent genes, 3) to understand how centromeres regulate distant genes by addressing centromere-mediated modulations of chromatin interactions and 4) validate the models emerging from our data using alternative and complementary methods. Upon completion of this project we expect to have identified a new centromere-dependent molecular mechanism regulating chromatin dynamics and transcription, which will provide deeper insight into general mechanisms of gene expression. We then plan on expending our scope to the role of centromeres in tumorigenesis and processing of harmful non-chromosomal DNA molecules by the cell.